The field of the invention relates to treatment of diseases and disorders associated with calcium/calmodulin dependent protein kinase II (CaMKII) activity. In particular the field of the invention relates to inhibition of mitochondrial CaMKII activity for treatment of diseases and disorders associated with mitochondrial CaMKII activity.
Mitochondria are structurally dynamic organelles which are known to initiate cell death. Myocardial-initiated cell death is caused by excess mitochondrial Ca2+ entry, leading to Ca2+ overload, mitochondrial permeability transition pore (mPTP) opening and dissipation of the mitochondrial inner membrane potential (ΔΨm). The multifunctional Ca2+ and calmodulin-dependent protein kinase II (CaMKII) is activated in ischemia reperfusion FR), myocardial infarction (MI) and neurohumoral injury which are all common causes of myocardial death and heart failure. This indicates that CaMKII links disease stress to mitochondrial injury. We recently reported that CaMKII promotes mPTP opening and myocardial death by increasing mitochondrial calcium uniporter (MCU) current (IMCU) (See Joiner et al. Nature, 2012. 491(7423):p. 269-73; and U.S. Provisional Patent Application No. 61/696,631). Mitochondrial-targeted CaMKII inhibitory protein, an mPTP antagonist with clinical efficacy in I/R injury, prevent mPTP opening, ΔΨm deterioration and diminishes mitochondrial disruption and programmed cell death in response to I/R injury. These findings identify CaMKII activity as a central component in the mechanism for mitochondrial Ca2+ entry and suggest mitochondrial-targeted CaMKII inhibition can prevent or reduce myocardial death and heart failure dysfunction in response to common experimental forms of pathophysiological stress.
Here, we disclose new mitochondrial-targeted reagents and a therapeutic strategy to treat or prevent mitochondria triggered cell death linked to over-activation of mitochondria via CaMKII activation of the MCU. The disclosed reagents will have broad application, not only to prevent or reduce myocardial death and heart failure dysfunction but also to other treat or prevent other diseases and disorders. This is because mitochondrial dysfunction underlies or contributes to many diseases and disorders including cancer (see O'Rourke, 2000, J. Physiol., 529:23-36; Zhao et al., 2012, Oncogene: doi:10.1038/one.2012.1494; and U.S. Provisional Patent Application No. 61/696,631), metabolic disease (see Herlein et al., 2010, Metabolism 59:247-257; and Jelenik & Roden, 2012, Antioxidants & Redox Signaling: doi:10.1089/ars.2012.4910), neurodegenerative diseases (see Johri & Beal, 2012, J. Pharma and Exper. Thera. 342: 619-630), and aging (see Wallace et al., 2010, Ann. Rev. Path.: Mech. of Disease, 5:297-348). To the best of the current inventors' knowledge, there are no known therapeutic treatments for mitochondria-based, CaMKII-associated diseases and disorders